Depletion of pancreatic lipid improves beta-cell function in early type 2 diabetes

胰腺脂质的消耗可改善早期 2 型糖尿病的 β 细胞功能

基本信息

批准号：
9902431
负责人：
W Timothy GARVEY
金额：
$ 53.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902431
关键词：
Address Adipose tissue Adult African American American Beta Cell Blood Glucose Body Composition Calories Cell physiology Cessation of life Characteristics Child Closure by clamp Development Diagnosis Diet Disease Disease Progression Disease remission Etiology European Event Failure Fat-Restricted Diet Fatty acid glycerol esters Food Glucose Clamp Guidelines Health Care Costs High Prevalence Hyperglycemia Individual Insulin Insulin Resistance Intervention Life Style Lipids Longevity Magnetic Resonance Imaging Metabolic Muscle National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Pancreas Participant Patients Pharmacotherapy Phase Populations at Risk Prediabetes syndrome Prevalence Quality of life Race Randomized Clinical Trials Recovery Research Risk Symptoms Testing Thigh structure Visceral Weight bariatric surgery blood glucose regulation cell injury clinical care design disability effective therapy ethnic difference experience glycemic control health disparity improved insulin secretion insulin sensitivity lean body mass non-diabetic patient population preservation prevent racial and ethnic response restoration subcutaneous sugar tool treatment response weight maintenance

项目摘要

The decline in first-phase insulin secretion is a key event in the etiology of type 2 diabetes (T2D). Although the cause of beta-cell failure is not clear, “lipotoxicity” has been proposed. Bariatric surgery and very-low calorie diets in patients with T2D induce disease remission, characterized by a return of first-phase insulin secretion and a depletion of pancreas lipid. However, these are extreme approaches to treating T2D, and non-invasive, sustainable, yet equally effective, treatments are needed. We have shown in individuals at risk for T2D that an intervention with a weight-maintaining low-glycemic (LG) diet selectively depletes visceral adipose tissue and ectopic lipid in muscle while preserving thigh subcutaneous adipose and lean body mass. This observation suggests that such diets are able to “remodel” body composition by re-partitioning energy away from metabolically harmful lipid stores. Participants on the LG diet also demonstrated improved insulin sensitivity and a dramatic (9-fold) increase in first-phase insulin secretion. Thus, we hypothesize that a weight-maintaining LG diet will selectively deplete ectopic adipose tissue, including pancreatic lipid, and will permit recovery of beta-cell function in individuals with T2D. Rescue of beta-cell function may be particularly important in African-Americans (AA), who as a group demonstrate a high prevalence of T2D, for reasons that cannot be explained by lifestyle. AA are likely to be vulnerable to beta-cell failure due to inherently high beta-cell responsiveness (demonstrable in healthy young children). Further, it has been shown that pancreas lipid is a determinant of prediabetes specifically in AA. Thus, we hypothesize that an LG diet will be particularly beneficial to beta-cell function and glycemic control among AA. To test these hypotheses, we will conduct a randomized clinical trial to examine the impact a weight-maintaining LG diet vs a Control diet (ADA/USDA) with all food provided on changes in pancreatic lipid by magnetic resonance imaging (MRI) and first-phase insulin secretion by hyperglycemic clamp and oral meal test in AA and European-American (EA) individuals with early T2D (<5 yr since diagnosis). The study will be powered to examine race-specific effects (race x diet interaction). This proposal responds to PA-17-021, “Addressing Health Disparities in NIDDK Diseases.” The results from this study could change clinical care guidelines to incorporate an LG diet, which may reduce the disproportionate burden of T2D and its complications experienced by AA.

第一相胰岛素分泌下降是 2 型糖尿病 (T2D) 病因学中的一个关键事件，尽管 β 细胞衰竭的原因尚不清楚，但已提出“减肥手术”和极低热量饮食。 T2D 患者的疾病缓解，其特征是第一阶段胰岛素分泌恢复和胰腺脂质消耗。然而，这些都是治疗 T2D 的极端方法，并且是非侵入性、可持续的，但同样有效。我们已经在有 T2D 风险的个体中证明，维持体重的低血糖 (LG) 饮食干预可以选择性地消耗内脏脂肪组织和肌肉中的异位脂质，同时保留大腿皮下脂肪和去脂体重。这一观察结果表明，这种饮食能够通过重新分配对代谢有害的脂质储存的能量来“重塑”身体成分，LG饮食的参与者还表现出胰岛素敏感性的改善和显着的改善。第一相胰岛素分泌增加（9 倍）因此，我们追求维持体重的 LG 饮食将选择性地消耗异位脂肪组织，包括胰腺脂质，并允许 T2D 患者恢复 β 细胞功能。 β 细胞功能的缺失对于非裔美国人 (AA) 可能尤其重要，他们作为一个群体表现出较高的 T2D 患病率，而 AA 很可能容易受到生活方式的影响。由于 β 细胞固有的高反应性（在健康幼儿中已得到证实），此外，研究表明，胰腺脂质是糖尿病前期的决定因素，特别是在 AA 中，因此，我们认为 LG 饮食对 β 细胞特别有益。为了检验这些假设，我们将进行一项随机临床试验，通过以下方法检验维持体重的 LG 饮食与控制饮食 (ADA/USDA) 对胰腺脂质变化的影响。磁共振成像 (MRI) 以及通过高血糖钳夹和口服膳食测试对 AA 和欧美 (EA) 早期 T2D 个体（诊断后 5 年内）的第一相胰岛素分泌进行检查该研究将有助于检查种族特异性。该提案响应 PA-17-021，“解决 NIDDK 疾病的健康差异”。这项研究的结果可能会改变临床护理指南，纳入 LG 饮食，从而可能减少AA 所经历的 T2D 及其并发症的不成比例的负担。